Huntington?sdisease:LearningfromExtremes Abstract:Huntington'sdisease(HD)isafatalgeneticneurodegenerativedisordercharacterizedbyprogressive motor, psychiatric and cognitive decline. It is caused by a genetic mutation leading to the global cellular expression of the mutant huntingtin protein (mtHtt), which is particularly toxic to the CNS. Disease modifying treatments are not yet available for this devastating and lethal disease. One of the challenges for designing efficient clinical trials isthe tremendous clinical variability that is observed. Much of that variability is contained in the markedly different rates of progression between subjects, which are likely caused by both genetic and environmentalfactors.VariableprogressionisnotexplainedbytheCAGexpansionlengthsincethevastmajority ofindividualswithHDfallinalimitedrangeofCAGlengthsspanning41-47yethaveagesofclinicalonsetfrom childhoodtothe8thdecadeoflife.Genome-wideassociationstudies(GWAS)haveuncoveredsomepotential and very limited contributions from other genes and do not explain the extremes observed clinically. We have studiednon-juvenileHDsubjectsmatchedforCAGnanddiseasedurationandhavingearlyandlateonsetand findthatearlieronsetisassociatedwithmorerapidcerebralatrophyandolderonsetwithslowercerebralatrophy, suggesting that age-of-onset is a strong predictor of the slope of progression. Understanding the biological factors that underlie divergent ages of onset and rates of progression may uncover correlates that enable understanding and predicting rates of progression and may help identify new treatment targets. We have previouslyidentifiedalteredmetabolomic,genetic,andtranscriptomicmarkersfromthebloodandinHDsubjects that represent pathways that could influence progression. We propose to expand our cohort of early and late onset subjects, evaluate their progression clinically and by neuroimaging, and to perform both unbiased and targetedstudiesofbloodandcsfmarkerstoseekdistinguishingcluestothevarianceinprogression.